Login using

You can login by using one of your existing accounts.

We will be provided with an authorization token (please note: passwords are not shared with us) and will sync your accounts for you. This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button.

SHARE ON

Review ARTICLE

Local control of striatal dopamine release

1Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA

2CHDI Foundation, Los Angeles, CA, USA

3Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

The mesolimbic and nigrostriatal dopamine (DA) systems play a key role in the physiology of reward seeking, motivation and motor control. Importantly, they are also involved in the pathophysiology of Parkinson’s and Huntington’s disease, schizophrenia and addiction. Control of DA release in the striatum is tightly linked to firing of DA neurons in the ventral tegmental area (VTA) and the substantia nigra (SN). However, local influences in the striatum affect release by exerting their action directly on axon terminals. For example, endogenous glutamatergic and cholinergic activity is sufficient to trigger striatal DA release independently of cell body firing. Recent developments involving genetic manipulation, pharmacological selectivity or selective stimulation have allowed for better characterization of these phenomena. Such termino-terminal forms of control of DA release transform considerably our understanding of the mesolimbic and nigrostriatal systems, and have strong implications as potential mechanisms to modify impaired control of DA release in the diseased brain. Here, we review these and related mechanisms and their implications in the physiology of ascending DA systems.

Introduction: Role of DA in Motor and Limbic Function

Dopamine (DA) plays a critical role in the organization of reward-seeking behavior and motor responses (Joshua et al., 2009; Schultz, 2013). Through the mesolimbic and nigrostriatal DA systems, the forebrain receives dopaminergic input that modulates a range of functionally distinct structures, such as the basal ganglia and cerebral cortex (Björklund and Dunnett, 2007; Tritsch and Sabatini, 2012). The mesolimbic system is formed by dopaminergic neurons located in the VTA and their projections to the nucleus accumbens (NAc), cortex, amygdala and hippocampus, which participate in the configuration of reward-seeking behaviors (Björklund and Dunnett, 2007; Stuber et al., 2012; Nieh et al., 2013). The nigrostriatal system has its origin in the substantia nigra pars compacta (SNc) and projects preferentially to the dorsolateral domains of the striatum, having a more defined role in the organization of motor plans (Groenewegen, 2003; DeLong and Wichmann, 2007). Such functional distinction at the level of the striatum seems to have structural and molecular correlates on DA neurons from the SNc (Henny et al., 2012; Schiemann et al., 2012). Additional to these functional implications, dopaminergic transmission is compromised in a variety of neurological conditions such as schizophrenia, Huntington’s and Parkinson’s disease, drug addiction and obsessive-compulsive disorder, among others (DeLong and Wichmann, 2007; Money and Stanwood, 2013).

DA modulation of incoming transmission to the striatum plays a key role in the functional expression of reward-seeking behaviors and motor control. Such functions exhibit some stratification within the striatum (Threlfell and Cragg, 2011). For example, dorso-medial and dorso-lateral areas are predominantly involved in motor control, while ventro-medial segments are mostly involved in the expression of reward processing, motivation and salience (Groenewegen, 2003; Voorn et al., 2004; Kreitzer and Berke, 2011; Stuber et al., 2012). Concurrently, cortico-striatal projections also exhibit a stratified distribution in which the motor and cingulate cortices form the primary input to the dorso-lateral striatum, while prefrontal and prelimbic cortices project mainly to ventro-medial areas of the striatum (Voorn et al., 2004). Phenomena responsible for regulation of striatal DA release can be VTA/SNc driven, or locally acting, at the striatal level. This latter possibility has long been reported, still attracts considerable attention in terms of mechanistic characterization (Cachope et al., 2012; Threlfell et al., 2012) and is considered as an opportunity for functionally-segregated intervention (Threlfell and Cragg, 2011).

Multiplicity of Mechanisms in the Control of Dopamine Release

Through what are now seminal papers, Wolfram Schultz et al. demonstrated that firing of DA neurons in the midbrain increases in response to rewarding stimuli in non-human primates (Schultz et al., 1997; Schultz, 1998), while functional imaging studies in humans point to a similar increase in cellular activity (D’Ardenne et al., 2008), suggesting correspondence with Schultz’s group reports. Interestingly, it was recently described that VTA GABAergic neurons also encode reward expectation (Cohen et al., 2012). Recordings of DA neurons from the VTA or SNc areas in rodents exhibit slow, tonic firing rates that periodically switch to a high frequency events (Grace and Bunney, 1984a, b). Thus, low levels of DA release have been correlated with low frequency firing rate of DA neurons, while corresponding enhancement in striatal DA release occurs in response to high frequency firing rates (Kawagoe et al., 1992). These findings have sculpted the traditional view of striatal DA release being determined by the rate of neuronal firing of the DA neuron somatas located in either VTA or SNc. However, besides this dominant mechanism of control of DA release, local factors such as reuptake, autoreceptor-dependent modulation, and termino-terminal control exist and are recognized to play a prominent role, independently of VTA/SNc firing rate.

DA neurons projecting to the striatum establish prominent axonal trees at their destination. The volume transmission feature of striatal DA implies that a considerable amount of control is required in terms of uptake and/or negative feedback on future release events. In reaching this goal, two key mechanisms are DA transporter activity (DAT) and D2-like presynaptic autoreceptor activity. DAT activity is thought to limit the radius of DA activity (Rice and Cragg, 2008) and, by doing so, restricts activation of DA receptors (reviewed in Rice et al., 2011). In a similar manner, it is known that blockade of D2-like DA receptors in slices leads to increased DA release in response to repetitive electrical stimulation (Limberger et al., 1991; Patel et al., 1992). This effect, however, is not manifest when single pulse stimulation is used (Limberger et al., 1991; Patel et al., 1992), suggesting that there is not sufficient DA tone elicited by a single pulse to be displaced by the antagonist. Importantly, changes in D2 receptor levels and their subsequent activation are thought to play a prominent role in several neurological conditions in which DA levels are altered (Ford, 2014).

Evidence on the potential role of glutamate as a form of local control of DA release in the striatum has long been reported (Imperato et al., 1990; Cheramy et al., 1991; Krebs et al., 1991; Desce et al., 1992) and both ionotropic and metabotropic glutamate receptors (iGluR; mGluR, respectively) have been implicated. However, most of the initial studies were performed in vivo using brain microdialysis as the measuring technique to assess DA levels as well as for local administration of glutamate receptor ligands. Such findings were of course influenced by slow temporal resolution and the effects of the ligand in a complex circuit, among other factors, making a mechanistic interpretation difficult. In vitro experimental designs, on the other hand, allowed for more direct mechanistic description while still not directly addressing whether results were equivalent to intact-tissue conditions. These distinct experimental conditions might account for what, at the time, were apparent contradictory results. Initial in vitro explorations in slices and synaptosomes accounted not only for glutamate, but for a range of neurotransmitters that could affect striatal DA release locally, including acetylcholine, GABA, glycine and opiates (reviewed in Chesselet, 1984). However, further in vivo experiments in freely moving rats were still non conclusive; i.e., activation of AMPA receptors by exogenous ligands led to a decrease in DA release, while an increase was evident only in response to the application of NMDA receptor ligands at high concentrations (Imperato et al., 1990). Blocking uptake of endogenous release, in turn, elevated DA release in a way that was sensitive to the application of either NMDA or AMPA antagonists, suggesting the involvement of both receptor types in that response (Segovia et al., 1997). Similarly, electrical stimulation of the prefrontal cortex, a putative glutamatergic input to striatum, as well as local application of kainate or NMDA increased DA release (Cheramy et al., 1991; Krebs et al., 1991). Development of electrochemical techniques, however, greatly contributed to the clarification of these mechanisms. The use of fast-scan cyclic voltammetry (FSCV) for the detection of DA in vitro allowed for better temporal resolution which was less influenced by circuit adaptive responses in the mid-term scale (minutes), which could potentially influence DA readout. Under those conditions, bath application of kainate, AMPA or NMDA elicited inhibition of DA release (Wu et al., 2000; Kulagina et al., 2001; Avshalumov et al., 2003). Moreover, electron microscopy studies were not able to demonstrate labeling of iGluRs in striatal DA terminals (Bernard et al., 1997; Bernard and Bolam, 1998). The lack of expression of iGluRs on DA terminals suggests that iGluR-mediated modulation of DA release relates to a more complex process; which may underlie interactions between multiple cellular types and/or chemical mediators. This issue, raised and investigated by Rice’s group led to the identification of H2O2 as a key molecule in the iGluR-mediated decrease of DA release (Avshalumov et al., 2000, 2003, 2008; Avshalumov and Rice, 2003). This model describes how glutamatergic activity on ionotropic receptors in medium spiny neurons (MSNs) triggers production and release of H2O2, which in turn diffuses to adjacent DA terminals and promotes opening of KATP channels leading to reduction of DA release (Avshalumov et al., 2008).

In contrast to iGluRs, labeling of mGluRs has been reported in presynaptic profiles identified as DA axons (Paquet and Smith, 2003). Moreover, blocking glutamate uptake, or high-frequency stimulation of the cortico-striatal pathway modulates DA release, in a mGluR-dependent fashion followed by modulation of Ca++-activated potassium channels (Zhang and Sulzer, 2003). Altogether, the existent evidence points to mGluR-mediated direct action on DA terminals, and a second MSN-mediated mechanism involving iGluR-H2O2 signaling.

Target receptors of cholinergic activity in the striatum are both of nicotinic and muscarinic types (nAChR and mAChR, respectively). While mAChRs are seven trans-membrane domain G-protein coupled receptors, nAChRs consist of five subunits arranged as homomers or heteromers that, in mammals, are formed by subfamilies II (α7) and III (α2-6, β2-4) (Le Novère et al., 2002). Particularly, striatal DA axons express a high density of α4, α5, α6, β2 and β3 subunits in an arrangement of two αβ pairs that could be α4-β2 and/or α6-β2 and/or α4-β4, plus a fifth subunit that can be α5 or β3 (Champtiaux et al., 2003; reviewed in Threlfell and Cragg, 2011). Additionally, the β2 subunit is expressed on striatal DA axons (Jones et al., 2001) and is included in all nAChRs at these terminals. This characterization is functionally relevant because some segregation exists in which predominance of different α subunits occurs between dorso-lateral striatum and the NAc. More specifically, a significant amount of work has shown that α4(non-α6)-nAChRs play a prominent role in dorsal striatum, while α4α6-nAChRs are dominant in NAc (Exley et al., 2008, 2011, 2012). Given the distinct functional role of the dorsolateral and the ventromedial striatum, it has been proposed that such differences could be taken into account as a substrate for region-specific intervention (Threlfell and Cragg, 2011).

mAChRs, in turn, are classified in two groups according to their coupling to either Gs (M1, M3, M5) or Gi (M2, M4) subunits of G proteins, with M2 and M4 predominantly expressed in CINs (Yan and Surmeier, 1996). In a similar way to what has been described for nAChRs, mAChRs exhibit some dorso-ventral gradient in their ability to regulate DA release. While M2/M4 receptors are necessary for such regulation in the dorsal striatum, M4 is prevalent in the NAc (Threlfell et al., 2010). Additionally, expression of M5 receptors has been reported in nigrostriatal DA neurons, although their pattern of expression on striatal DA terminals and subsequent potential role in local control of DA release remains unclear (reviewed in Threlfell and Cragg, 2011; Zhang and Sulzer, 2012).

Involvement of presynaptic cholinergic receptors on DA regulation was inferred early, mainly from experiments describing increase of DA release in response to AChR activation in slices or synaptosomes (Giorguieff et al., 1976, 1977; Wonnacott et al., 1989; Rapier et al., 1990). In a similar way to what occurred with the characterization of glutamatergic-dependent DA modulation, transition to electrochemical methods to quantify DA allowed for a better temporal resolution. Importantly, FSCV has been critical in determining a high dependence of DA release on stimulation frequency under the effect of nicotine. More specifically, in a striatal slice, the maximum peak of DA release does not change significantly through different frequencies (5, 10, 25, 50 Hz) of electrical stimulation. However, in the presence of nicotine or the nAChR antagonist mecamylamine, DA release at low frequencies is decreased, while at high frequencies release is enhanced (Rice and Cragg, 2004).

In the case of mAChRs, they can also locally modulate DA release in the striatum. In vitro experiments with FSCV show how a wide range mAChR antagonist (oxotremorine) decreases DA release evoked by single pulse electrical stimulation, but enhances DA levels in response to train stimulation (Threlfell et al., 2010). A similar effect was observed using selective optogenetic stimulation, in which single pulse optical stimulation did not affect DA release, but instead 5 and 10 Hz stimulation enhanced DA release under application of the mAChR antagonist scopolamine (Cachope et al., 2012; Threlfell et al., 2012).

A complex interaction between diverse neurotransmission and neuromodulatory systems takes place in the control of striatal DA release. Although we have focused on the effect of glutamatergic and cholinergic systems, a handful other receptors have been identified as able to alter striatal DA levels; including GABA, cannabinoid, purinergic and opioid. Interestingly (and, up to some point expected), the possibilities for diversity on this local control are dependent on the type of receptor, not just the type of transmitter/modulator being released. Both in the case of glutamate and acetylcholine, different receptors lead to distinct and even opposite effects. As illustrated in Figure 1, mGluR activation on DA terminals and iGluR activation on MSNs result both in modulation of K conductances decreasing DA release. In contrast, activation of nAChRs on DA terminals leads to increased DA release, while activation of mAChR autoreceptors expectedly result in decreased DA release. More importantly, all these results demonstrate that firing rate at the VTA and SNc does not entirely determine striatal DA output, leaving enough room for control mechanisms driven by input from other areas (glutamatergic), as well as by interneurons (cholinergic), which might exert considerable impact on it.

Concluding Remarks

The role of DA in essential behaviors such as reward-seeking, motivation and motor control has been extensively studied. Regulation of DA release at both the dorso-lateral striatum and the NAc is considered to be mainly the consequence of changes in firing rate at the level of DA somata in the SNc and the VTA, correspondingly. Local control at the level of the striatum has been traditionally linked to DA reuptake and to feedback control on DA release through activation of D2 autoreceptors. However, reports on termino-terminal control of DA release, although scarce decades ago provided key findings in understanding a more complex control system than the one defined just by firing rate at DA neuronal somata. To date, the influence of non-DA striatal terminals on striatal DA release has been explored in a variety of experimental conditions, including synaptosomes, in vitro slices and in vivo preparations. Not only pharmacological, but genetic, optogenetic, electrophysiological and electrochemical strategies have been used to unveil the localization, role, extent and functional impact of such local influences. Glutamatergic and cholinergic systems have attracted the most attention so far. Still, although highly characterized in terms of types of receptors and neurotransmitters involved, there is not enough evidence on the functional impact of these forms of regulation in the behavioral setting. CINs modify their firing rate in animals subject to behavioral tasks encoding reward delivery as a decrease in firing rate, following a mild increase in frequency of firing (Apicella et al., 1991, 2011; Aosaki et al., 1994; Shimo and Hikosaka, 2001; Morris et al., 2004). Also, a recent report shows a differential role of DA neurons modulating CINs firing in dorsal striatum and NAc (Chuhma et al., 2014). However, there is no clarity as to how prominent all those interactions are in terms of their ability to affect DA release, and even less is known about the role of such variations, if they might impact behavior, or if DA transmission is otherwise still VTA- and SNc-driven.

One of the main strategies to fully develop yet is the potential of targeting these modulation systems to affect striatal DA release in conditions such as Parkinson’s disease, schizophrenia, addiction, Huntington’s disease, in which DA levels have been reported to be altered. As already outlined by Threlfell and Cragg (2011), modulating the striatal cholinergic system through subunit-specific modulation of nAChR and mAChR promises to be a useful approach. Temporal dynamics are a critical feature of inter-neuronal transmission. Behavioral events have, for example, phasic changes in striatal DA levels as correlates in the limbic and motor areas (O’Neill and Fillenz, 1985; Schultz, 2007a, b; Joshua et al., 2009). A significant proportion of therapeutic strategies are based on ligands that exert a sustained effect on neurotransmitter receptors, cancelling such changes over time. While DA neuron somata drive phasic changes in DA release, termino-terminal control might be seen as a mechanism that allows for fine regulation over that main drive, still preserving most of the temporal dynamics.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Bernard, V., and Bolam, J. P. (1998). Subcellular and subsynaptic distribution of the NR1 subunit of the NMDA receptor in the neostriatum and globus pallidus of the rat: co-localization at synapses with the GluR2/3 subunit of the AMPA receptor. Eur. J. Neurosci. 10, 3721–3736. doi: 10.1046/j.1460-9568.1998.00380.x